A hallmark of most urea cycle disorders (UCDs) is the toxic accumulation of ammonia that ultimately leads to a number of clinical features, including cognitive impairment. Accordingly, treatment for UCD patients involves daily oral intake of ammonia scavenging drugs, including sodium phenylbutyrate (SPB) and/or glycerol phenylbutryate (GPB) which go by the trade names BUPHENYLŪ and RAVICITIŪ, respectively. Once consumed, both SPB and GPB are converted to phenylacetate, a compound that scavenges ammonia through the formation of the urine excreted metabolite phenylacetylglutamine (PAG) (1-3). Sodium phenylbutyrate is also in phase I clinical trials for the treatment of Parkinson disease to slow progression of disease and to reduce death of dopaminergic neurons (4, 5).

Key to successful treatment of UCDs is the accurate monitoring of patient compliance and ammonia removal. Unfortunately, even under optimal conditions, a patient?s daily plasma ammonia levels can fluctuate by as much as 10-fold, rendering it an inexact diagnostic value for clinical management (2, 3). Instead, urinary excretion of PAG has been proposed as a dosing biomarker based on the strong correlation between urine excreted PAG and daily intake of phenylbutyrate (3). To allow comprehensive monitoring of UCD patients, our assays measure urine, plasma, and CSF levels of PAG and its upstream precursors phenylbutyrate and phenylacetate.